Clinical psychologists and psychiatrists have come to emphasize the importance of effort-related symptoms, such as anergia, apathy, and fatigue, in major depression. Nevertheless, despite the large number of tests that are currently available for the assessment of antidepressant drugs in animal models, none of the widely used tasks is specifically focused upon effort-related functions in animals. Over the last few years, our laboratory has developed behavioral models in animals that are useful for assessing the role of various neurotransmitters, such as dopamine (DA) and adenosine, in the exertion of effort and effort-related choice behavior. Considerable evidence indicates that these basic studies in animals are potentially relevant for understanding effort-related dysfunction in humans. However, it is critical to determine if these procedures can lead to the development of novel models of the effort- related symptoms of depression. For these reasons, the goal of the proposed investigation is to study the ability of several conditions that are related to depression to induce effort-related dysfunctions in rats. One group of studies will assess the effects of low doses of the monoamine-depleting agent reserpine on tasks involving exertion of effort and effort-related choice behavior. Additional experiments will study the behavioral characteristics of two genetic models of depression (Congenitally Helpless Rats; Flinders Sensitive line rats). The final group of studies will assess the effects of a novel treatment strategy for depression (adenosine A2A antagonists) and two well known drugs (bupropion and fluoxetine), using behavioral models of effort-related function. The proposed experiments are designed to test the feasibility of using these procedures as potential models of the effort-related symptoms of depression and other disorders. PUBLIC HEALTH RELEVANCE: Organisms are separated from significant stimuli such as food by environmental constraints or obstacles, and therefore motivated behaviors often are characterized by a high degree of vigor, persistence and work output. Moreover, organisms continually make effort-related decisions based upon cost/benefit analyses. In the clinical literature, psychiatrists and psychologists have come to emphasize the importance of energy-related dysfunctions, such as anergia and fatigue, in major depression, Parkinsonism and other disorders. It is critical to determine if animal procedures can lead to the development of novel models of the effort-related symptoms of depression. For these reasons, the goal of the proposed investigation is to study the ability of pharmacological and genetic conditions that are related to depressive symptoms to induce effort-related dysfunctions in rats. It is vital to study the brain mechanisms that are involved in effort-related processes, because such studies provide information about a fundamental aspect of motivation, and also because they could lead to the development of novel treatments for fatigue-related disorders.